The objective of this application is the testing for efficacy of a model live herpes simplex virus (HSV) vaccine, represented by an acyclovir-resistant (ACVr), thymidine-kinase negative (TK-) and latency-negative HSV type 1 mutant. The experiments will test the hypothesis that an effective protection against the establishment of latent infections in sensory ganglia by wild HSV strains can be obtained only by their prior colonization with a latency negative mutant. Although viewed with some reservations, the development of a live HSV vaccine may prove to be the only way to stem the spread of the infection to susceptible persons, which otherwise would be added to the millions of individuals already suffering from recurrent herpes caused by reactivation of latent virus in sensory ganglia. As experimental animals we will use hairless mice, well suited for monitoring virus-induced skin lesions and in which the colonization of ganglia with HSV is easily achieved. Experiments will be designed (a) to determine the dose of mutant virus and number of inoculations required to obtain protection; (b) to examine whether inoculation with the mutant on one site will provide protection against reinfection at a different site (anterior vs. posterior, left vs. right); (c) to determine the inoculation site(s) providing protection against reinfection at any site; and (d) to determine whether the mutant HSV-1 can protect against reinfection with a wild HSV-2 strain. It is expected that the data will provide important information on the requirements for an effective HSV vaccination.